The long-term objectives of the proposed research are to define the organization of the autonomic innervation to the pancreas and its role in regulating pancreatic exocrine and endocrine secretion. The experiments described will focus synaptic transmission in pancreatic ganglia which contain the postganglionic parasympathetic neurons innervating exocrine and endocrine cells as well as the pancreatic ducts. Our working hypothesis is that pancreatic ganglia are a critical yet unexplored site where parasympathetic, sympathetic, enteric, and sensory nerves can act and interact to regulate postganglionic firing and thus secretion. The specific aims of the project will involve studying the electrophysiologic effects of neurotransmitters predominantly or exclusively contained in nerve fibers from one of these branches of the nervous system as a means of evaluating the functional role of these fibers in ganglionic transmission. The transmitters to be studied include: 1) Vasoactive intestinal polypeptide (VIP), predominantly co-contained with acetylcholine in postganglionic pancreatic neurons, 2) Norepinephrine (NE), exclusively contained in postganglionic sympathetic nerve fibers, and 3) Serotonin (5-HT) contained in enteric nerves from stomach and duodenum, 4) Substance P (SP) and calcitonin gene-related peptide (CGRP) predominantly contained in the peripheral processes of primary afferent nerves. Intracellular recordings will be performed in single neurons from intact cat pancreatic ganglia and transmitters will be applied by pressure ejection or superfusion. Effects on postsynaptic excitability will be determined from measurements of resting membrane potential, input resistance, shape of action potentials, and firing patterns in response to prolonged intracellular stimuli or trains of stimuli. The voltage-and ionic-dependence of these responses will then be characterized. A role for endogenous release of each of the transmitters will be demonstrated by antagonizing synaptically evoked potentials using specific receptor antagonists when available or by desensitizing neurons with continued application of the transmitter under study. The interactions of the exogenously applied or synaptically released transmitters with other (cholinergic, adrenergic, non-adrenergic non-cholinergic) synaptic potentials will also be tested. The significance of the work proposed here is the study of a critical yet previously unexplored site of neural control of pancreatic secretion. Neurons in pancreatic ganglia occupy a crucial position in the flow of information from a variety of neural sources to the secretory cells. Only by the use of intracellular recordings to study synaptic transmission can the functional consequences of activating these pathways be understood. Thus, the experiments described are essential for understanding neural control of pancreatic secretion as well as the functional implications of pancreatic neuropathies observed in diseases such as diabetes mellitus and chronic pancreatitis.